Targeting the heme-oxidized nitric oxide receptor for selective vasodilatation of diseased blood vessels.

ROS are a risk factor of several cardiovascular disorders and interfere with NO/soluble guanylyl cyclase/cyclic GMP (NO/sGC/cGMP) signaling through scavenging of NO and formation of the strong oxidant peroxynitrite. Increased oxidative stress affects the heme-containing NO receptor sGC by both decreasing its expression levels and impairing NO-induced activation, making vasodilator therapy with NO donors less effective. Here we show in vivo that oxidative stress and related vascular disease states, including human diabetes mellitus, led to an sGC that was indistinguishable from the in vitro oxidized/heme-free enzyme. This sGC variant represents what we believe to be a novel cGMP signaling entity that is unresponsive to NO and prone to degradation. Whereas high-affinity ligands for the unoccupied heme pocket of sGC such as zinc-protoporphyrin IX and the novel NO-independent sGC activator 4-[((4-carboxybutyl){2-[(4-phenethylbenzyl)oxy]phenethyl}amino) methyl [benzoic]acid (BAY 58-2667) stabilized the enzyme, only the latter activated the NO-insensitive sGC variant. Importantly, in isolated cells, in blood vessels, and in vivo, BAY 58-2667 was more effective and potentiated under pathophysiological and oxidative stress conditions. This therapeutic principle preferentially dilates diseased versus normal blood vessels and may have far-reaching implications for the currently investigated clinical use of BAY 58-2667 as a unique diagnostic tool and highly innovative vascular therapy.

Edaravone attenuates hydroxyl radical stress and augmented angiotensin II response in diabetic rats.

Reactive oxygen species (ROS) potentiate angiotensin II (Ang II) responses in diabetic vasculature. However, superoxide scavengers partially restore this effect, suggesting free radicals other than superoxide could be involved. Edaravone (3-methyl-1-phenyl-2-pyrazolin-5-one) is an antioxidant, which primarily scavenges hydroxyl radicals and is approved for use in stroke patients. Hence, to evaluate the role of hydroxyl radical stress in diabetic vascular complications, we studied the effect of edaravone (3 mgkg(-1), i.p., b.i.d.) treatment on Ang II responses in thoracic aorta isolated from streptozotocin (60 mgkg(-1) i.p.) induced 8 weeks diabetic male Sprague-Dawley rats. Ang II (10(-10) to 10(-6)M), tert-butyl hydro peroxide (tBHP; 10(-6) to 10(-2)M) or hydrogen peroxide (H2O2; 10(-6) to 10(-3)M) induced contractile response was significantly enhanced in aortic strips from diabetic as compared to control rats. Lipid peroxidation was significantly enhanced while the superoxide dismutase (SOD) and catalase activity was significantly lower in aorta of diabetic rats as compared to control rats. Acute (in vitro) exposure of edaravone (10(-5)M) to aortic strips from diabetic rats in the organ bath restored the augmented Ang II but not tBHP or H2O2-induced contractile response. In vivo edaravone (3mgkg(-1), i.p., b.i.d.) treatment for 2 weeks selectively attenuated the augmented Ang II- but not tBHP- or H2O2-induced contractile response. The enhanced systolic pressure, lipid peroxidation and the reduced SOD and catalase activity were restored to control values following 2 weeks edaravone treatment. From our results we infer that hydroxyl radical stress augments Ang II response in diabetic rat thoracic aorta and edaravone could be an ideal antioxidant adjuvant in the therapy of diabetic vascular complications.